Epoxysuccinamic acid derivatives

ABSTRACT

An epoxysuccinamic acid derivartive represented by the formula: ##STR1## (wherein R 1  is an alkyl group having 1 to 10 carbon atoms, a phenyl group or a benzyl group), a pharmaceutically acceptable salt thereof, and an intermediate thereof are disclosed The compound of Formula I is useful as a therapeutical agent for muscular atrophy diseases.

TECHNICAL FIELD

The present invention relates to epoxysuccinamic acid derivatives usefulas medicines, and more particularly to epoxysuccinamic acid derivativesinhibiting cathepsin B specifically, and the preparation intermediatesthereof.

BACKGROUND ART

Calcium-activated neutral protease (CANP), cathepsin B and cathepsin L,each of which belongs to cysteine proteases, are considered to beassociated with the decomposition of muscular structure protein inmalignant muscular atrophy diseases such as muscular dystrophy anddistal myopathy.

Some epoxysuccinic acid derivatives such asN-(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucylagmatine

[Agric. Biol. Chem., vol. 42, pp. 523-528 (1978)], epoxysuccinyldipeptide derivatives (U.K. Patent No. 2,046,730) and the like have beenheretofore known as the compound inhibiting several thiol proteases.However, no epoxysuccinic acid derivatives inhibiting specifically onlyone of the cysteine proteases have been known.

As a result of the earnest research to compounds having an epoxy ring,the present inventors have found the compounds inhibiting cathepsin Bally unlike the known compounds, and have accomplished the presentinvention.

DISCLOSURE OF THE INVENTION

The present invention is an epoxysuccinamic acid derivative representedby Formula I: ##STR2## (wherein R¹ is an alkyl group having 1 to 10carbon atoms, a phenyl group or a benzyl group) and a pharmaceuticallyacceptable salt thereof.

In addition, the present invention is an epoxysuccinamic acid derivativerepresented by Formula II: ##STR3## (wherein R¹ is as defined above, R²is a protecting group of the carboxyl group), which is a preparationintermediate of the compound of Formula I.

In the present invention, the alkyl group having 1 to 10 carbon atomsrefers to a straight chain, branched chain or cyclic alkyl group suchas, for example, a methyl group, an ethyl group, an n-propyl group, ann-butyl group, an n-pentyl group, an isopropyl group, an isobutyl group,a t-butyl group and a cyclohexyl group, and preferably an n-propyl groupand an n-pentyl group. The protecting group of the carboxyl group refersto those used usually in the field of the peptide synthesis chemistry,for example, a benzyl group, a p-methoxybenzyl group, a p-nitrobenzylgroup, a t-butyl group, a benzhydryl group, a trimethylsilyl group, amethyl group and an ethyl group.

The pharmaceutically acceptable salts of the present invention are saltswith inorganic bases including sodium, potassium, magnesium, ammoniumand the like, salts with organic bases or basic amino acids (e.g.triethylamine, cyclohexylamine, arginine and lysine), salts with mineralacids (e.g. sulfuric acid, hydrochloric acid and phosphoric acid), saltswith organic acids and acidic amino acids (e.g. acetic acid, lacticacid, tartaric acid, fumaric acid, maleic acid, glutamic acid andaspartic acid).

The compounds of the present invention can be prepared, for example, bythe following processes (in the following formulae, R¹ and R² are asdefined above, and R² and R³ may be the same or different, and each ofwhich is a protecting group of the carboxyl group). ##STR4##

Process (a): An epoxysuccinic acid derivative of Formula III which canbe prepared according to the method described in Chem. Pharm. Bull.,vol. 35, pp. 1098-1104 (1987), is reacted with 1.0-2.0 molar equivalentsof an amine of Formula IV in a solvent such as chloroform, ethyl acetateand N,N-dimethylformamide to give a compound of Formula V.

Process (b): The protecting group of the carboxyl group of the compoundof formula V is removed in a solvent such as methanol, ethanol andN,N-dimethylformamide according to a method and conditions used usuallyin the field of the peptide synthesis chemistry such as a catalyticreduction using a catalyst such as palladium carbon and palladium black,a catalytic transfer hydrogenation (CTH) or hydrolysis using an acid(e.g. trifluoroacetic acid, methanesulfonic acid, hydrobromic acid andhydrochloric acid) or a base (e.g. sodium hydroxide and potassiumhydroxide) to give a compound of Formula VI.

Process (c): A dipeptide derivative of Formula VII, which can beprepared by using isoleucine and proline according to a method usedusually in the field of the peptide synthesis chemistry, is condensedwith 1.0-2.0 molar equivalents of a compound of Formula VI in a solventsuch as chloroform, ethyl acetate and N,N-dimethylformamide according toa method and conditions used usually in the field of the peptidesynthesis chemistry such as a method using a carbodiimide compound (e.g.N,N'-dicyclohexylcarbodiimide andN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride), a mixedanhydride method, a acid halide method, an azide method and an activatedester method to give a compound of Formula II of the present invention.

Process (d): The protecting group of a carboxyl group of the compound ofFormula II is removed by the same method and conditions as used inProcess (b) to give a compound of Formula I of the present invention.

Furthermore, the amine of Formula IV and the dipeptide derivative ofFormula VII may be each used in the form of a salt such as salts withhydrochloric acid, sulfuric acid and p-toluenesulfonic acid. In thiscase, the reaction may be carried out in the presence of a base such astriethylamine, N,N-diisopropylethylamine, N-methylmorpholine andpyridine.

The compounds of Formula I thus obtained hardly inhibit papain and CANPwhich belong to cysteine proteases, but strongly inhibit cathepsin Bspecifically.

The experiments are shown below.

EXPERIMENTS

The inhibitory activities against papain, CANP and cathepsin B weremeasured according to the following methods, and results are shown inTable 1.

EXPERIMENT 1 Inhibitory Activity Against Papain

The measurement was carried out according to the method of A. J. Barrettet al [Biochem. J., vol. 201, p. 189 (1982)].

To each of 0.95 ml of the reaction solutions containing 2.5 mM2-mercaptoethanol, 1 mM disodium ethylenediaminetetraacetate, 0.1 Msodium potassium phosphate buffer (pH 6.8), 0.1% Brij-35 (produced byNacalai Tesque Inc.), 1% dimethyl sulfoxide and various concentrationsof the test drug was added 25 μl of a papain solution (produced by SigmaChemical Co.), and the mixture was preincubated at 40° C. for 3 minutes,after which 25 μl of 200 μM benzyloxycarbonyl-L-phenylalanyl-L-arginine4-methylcoumaryl-7-amide (produced by Peptide Institute Inc.) was addedfor starting the reaction After incubation at 40° C. for 10 minutes, thereaction was stopped by addition of 1 ml of 100 mM sodium acetate buffersolution (pH 4.3) containing 100 mM sodium chloroacetate. Thefluorescence of the liberated 7-amino-4-methylcoumarine was determinedusing a Shimazu fluorometer RF-5000 with excitation at 380 nm andemission measured at 440 nm. The concentration of the test drug requiredfor 50% inhibition (IC₅₀) was calculated from the inhibition ratecalculated using the value which was measured in a similar manner to theabove but without the test drug.

EXPERIMENT 2 Inhibitory Activity Against CANP

The measurement was carried out according to the method of S. Ishiura etal (J. Biochem., vol. 84, p. 225 (1978)].

Each of 0.45 ml of the reaction solutions containing 25 mM2-mercaptoethanol, 5 mM calcium chloride, 0.1 M sodiumglycerophosphate-HCl buffer (pH 7.5), 0.24% alkali-denatured casein, 1%dimethylsulfoxide and various concentrations of the test drug waspreincubated accurately at 30° C. for 5 minutes, and 50 μl of a solutioncontaining 5 μg of μ CANP (Calpain I, produced by Nacalai Tesque Inc.)was added for starting the reaction. After exact incubation at 30° C.for 20 minutes, the reaction was stopped by addition of 0.5 ml of 10%trichloroacetic acid. After being allowed to stand at room temperaturefor 60 minutes, the mixture was centrifuged at 3000 × g for 5 minutes,and the absorbance at 280 nm of the supernatant was determined. Theremaining activity was obtained by reducing the blank value which wasobtained in a similar manner to the above but adding 10% trichloroaceticacid prior to addition of μ CANP from the above value. The concentrationof the test drug required for 50% inhibition (IC₅₀) was calculated fromthe inhibition rate obtained using the value which was measured in asimilar manner to the above but without the test drug.

EXPERIMENT 3 Inhibitory Activity against Cathepsin B

The measurement was carried out according to the method of A. J. Barrettet al [Biochem. J., vol. 201, page 189 (1982)].

To each of 0.95 ml of the reaction solutions containing 2.5 mM2-mercaptoethanol, 1 mM disodium ethylenediaminetetraacetate, 0.1 Msodium potassium phosphate buffer (pH 6.0), 0.1% Brij-35 (produced byNacalai Tesque Inc.), 1% dimethyl sulfoxide and various concentrationsof the test drug was added 25 μl of 200 nM cathepsin B solution(produced by Sigma Chemical Co.), and the mixture was preincubated at40° C. for 3 minutes, after which 25 μl of 200 μMbenzyloxycarbonyl-L-phenylalanyl-L-arginine 4-methylcoumaryl-7-amide(produced by Peptide Institute Inc.) was added for starting the reactionAfter incubation at 40° C. for 10 minutes, the reaction was stopped byaddition of 1 ml of 100 mM sodium acetate buffer (pH 4.3) containing 100nM sodium chloroacetate. The fluorescence of the liberated7-amino-4-methyl-coumarine was determined using a Shimazu fluorometerRP-5000 with excitation at 380 nm and emission measured at 440 nm. Theconcentration of the test drug required for 50% inhibition (IC₅₀) wascalculated from the inhibiting rate calculated using the value which wasmeasured in a similar manner to the above but without the test drug.

                  TABLE 1                                                         ______________________________________                                        Inhibitory Activity Value [IC.sub.50 (nM)]                                    Test drug                                                                     (Compound No.)                                                                             Papain    CANP     Cathepsin B                                   ______________________________________                                        1d           57,400    >200,000 42                                            8d           26,000    >200,000 32                                            ______________________________________                                         (Note)                                                                        The test drugs in the table are the compounds which are obtained in the       following examples.                                                      

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter illustrated in more detail by thefollowing examples.

EXAMPLE 1

(a) To a solution of 2.0 g (5.8 mM) of L-trans-epoxysuccinic acid benzylp-nitrophenyl ester in 13 ml of ethyl acetate was added dropwise asolution of 413 mg (7.0 mM) of n-propylamine in 2 ml of ethyl acetateunder ice cooling with stirring and further stirring was continued underice cooling for an hour and at room temperature overnight. Then, 85 mlof ethyl acetate was added, and the mixture was washed successively with100 ml each of 1N ammonia water, water, 5% aqueous hydrochloric acidsolution, water and a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was chromatographed on asilica gel column (eluent; ethyl acetate : n-hexane =1:2) to give 1.08 gof L-3-trans-n-propyl-carbamoyloxirane-2-carboxylic acid benzyl ester.

NMR (DMSO-d₆) δ(ppm);

0.83(3H, t, J=7.3Hz),

1.43(3H, tq, J=7.3, 7.3Hz),

3.05(2H, dt, J=5.4, 7.3Hz),

3.63(1H, d, J=1.8Hz), 3.68(1H, d, J=1.8Hz),

5.20(2H,s), 7.39(5H, s),

8.39(1H, t, J=5.4Hz)

IR ν_(max) ^(KBr) cm⁻¹ ;

3284, 1749, 1661, 1568, 1346, 1282, 1233, 1208,

898

(b) To a suspension of 20 mg of 10% palladium carbon in 20 ml ofmethanol was added 851 mg (3.2 mM) ofL-3-trans-n-propylcarbamoyloxirane-2-carboxylic acid benzyl ester, andstirring was continued under a hydrogen atmosphere for 2 hours Thepalladium carbon was filtered off, and washed with methanol The filtrateand the washings were combined and evaporated under reduced pressure togive 550 mg of L-3-trans-n-propylcarbamoyloxirane-2-carboxylic acid.

NMR (DMSO-d₆) δ(ppm);

0.84(3H, t, J=7.3Hz),

1.43(2H, tq, J=7.3, 7.3Hz),

3.06(2H, dt, J=5.4, 7.3Hz),

3.46(1H, d, J=1.8Hz), 3.53(1H, d, J=1.8Hz),

8.34(1H, t, J=5.4Hz),

12.50˜14.35(1H, broad)

IR ν_(max) ^(KB4) cm⁻¹ ;

3318, 2964, 1768, 1651, 1582, 1455, 1382, 1348,

1274, 1242, 1220, 1151, 984, 894

(c) To a solution of 500 mg (2.9 mM) ofL-3-trans-n-propylcarbamoyloxirane-2-carboxylic acid, 1.04 g (2.9 mM) ofL-isoleucyl-L-proline benzyl ester hydrochloride, 365 mg (3.2 mM) ofN-hydroxysuccinimide and 609 mg (3.2 mM) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 13 ml ofN,N-dimethylformamide was added dropwise a solution of 293 mg (2.9 mM)of N-methylmorpholine in 2 ml of N,N-dimethylformamide under ice coolingwith stirring, and further stirring was continued under ice cooling foran hour and at room temperature overnight. To the reaction mixture wasadded 150 ml of a mixture of ethyl acetate and benzene (4:1), and themixture was washed successively with 150 ml each of 5% aqueoushydrochloric acid solution, water, a saturated aqueous sodiumbicarbonate solution, water and a saturated aqueous sodium chloridesolution The organic layer was dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure The residue waschromatographed on a silica gel column (eluent; ethyl acetate n-hexane=4:1) to give 830 mg ofN-(L-3-trans-n-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-prolinebenzyl ester.

NMR (DMSO-d₆) δ(ppm);

0.72˜0.90 (9H, m), 0.96˜1.22(1H, m),

1.36˜1.56(1H, m),

1.42(2H, tq, J=7.3, 7.3Hz),

1 65˜2.00(4H, m), 2.10˜2.28(1H, m),

2.94˜3.12(2H, m), 3.47(1H, d, J=1.8Hz),

3.52˜3.85(2H, m), 3.65(1H, d, J=1.8Hz),

4.35˜4.49(2H, m), 5.12(2H, s), 7.36(5H, s),

8.32(1H, t, J=5.7Hz), 8.75(1H, d, J=8.4Hz)

IR ν_(max) ^(CHCl) ₃ cm⁻¹ ;

2969, 1742, 1685, 1645, 1520, 1447, 1276, 1238,

1174, 898

MS (FAB); m/z:474(M⁺)

(d) To a suspension of 20 mg of 10% palladium carbon in 20 ml ofmethanol was added 690 mg (1.5 mM) ofN-(L-3-trans-n-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-prolinebenzyl ester, and stirring was continued under a hydrogen atmosphere foran hour. The palladium carbon was filtered off, and washed withmethanol. The filtrate and washings were combined and evaporated underreduced pressure to give 500 mg ofN-(L-3-trans-n-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline(Compound 1d).

NMR (DMSO-d₆) δ(ppm);

0.84(6H, t, J=7.3Hz), 0.92(3H, d, J=6.8Hz),

0.96˜1.20(1H, m), 1.38 .1.58(1H, m),

1.42(2H, tq, J=7.3, 7.3Hz),

1.67˜2.01(4H, m), 2.05˜2.21(1H, m),

2.95˜3.14(2H, m), 3.48(1H, d, J=1.8Hz),

3.50˜3.83(2H, m), 3.65(1H, d, J=1.8Hz),

4.20˜4.30(1H, m),

4.42(1H, dd, J=8,5, 8.5Hz),

8.32(1H, t, J=5.7Hz), 8.72(1H, d, J=8.5Hz),

12.00˜13.20(1H, broad)

IR ν^(KBr) _(max) cm⁻¹ ;

3285, 2969, 1733, 1630, 1546, 1452, 1324, 1228,

1193, 1049, 898

MS (FAB); m/z: 384(MH⁺)

Following the procedure and reaction condition disclosed in Example lausing ethylamine, isopropylamine, t-butylamine, isobutylamine,n-butylamine, isoamylamine, n-amylamine, n-hexylamine, n-heptylamine,benzylamine, aniline or cyclohexylamine in place of n-propylamine, therewere obtained the compounds shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR5##                                                                     Compound No.                                                                          R.sup.1   NMR (DMSO-d.sub.6) δ(ppm)                                                            IR(cm.sup.-1)                                  __________________________________________________________________________    2a      CH.sub.3 CH.sub.2                                                                       1.14(3H, t, J=7.3Hz)                                                                       (KBr)                                                            3.21˜3.38(2H, m)                                                                     3286                                                             3.51(1H, d, J=1.9Hz)                                                                       1748                                                             3.69(1H, d, J=1.9Hz)                                                                       1656                                                             5.17(1H, d, J=12.1Hz)                                                                      1572                                                             5.26(1H, d, J=12.1Hz)                                                                      1384                                                             5.90˜6.15(1H, broad)                                                                 1340                                                             7.37(5H, s)  1275                                                                          1233                                                                          1207                                                                          894                                            3a      (CH.sub.3).sub.2 CH                                                                     1.12(3H, d, J=6.6Hz)                                                                       (KBr)                                                            1.17(3H, d, J=6.6Hz)                                                                       3286                                                             3.49(1H, d, J=1.9Hz)                                                                       1749                                                             3.67(1H, d, J=1.9Hz)                                                                       1656                                                             3.93˜4.18(1H, m)                                                                     1561                                                             5.17(1H, d, J=12.1Hz)                                                                      1352                                                             5.26(1H, d, J=12.1Hz)                                                                      1268                                                             5.75˜5.95(1H, broad)                                                                 1232                                                             7.37(5H, s)  1206                                                                          898                                            4a      (CH.sub.3).sub.3 C                                                                      1.27(9H, s)  3306                                                                              (neat)                                                       3.63(1H, d, J=1.9Hz)                                                                       2971                                                             3.64(1H, d, J=1.9Hz)                                                                       1752                                                             5.16(1H, d, J=12.3Hz)                                                                      1668                                                             5.23(1H, d, J=12.3Hz)                                                                      1551                                                             7.28˜7.53(5H, m)                                                                     1457                                                             8.08(1H, bs) 1366                                                                          1279                                                                          1217                                                                          1192                                                                          1003                                                                          897                                            5a      (CH.sub.3).sub.2 CHCH.sub.2                                                             0.84(6H, d, J=6.7Hz)                                                                       3274                                                                              (KBr)                                                        1.70(1H, tqq, J=6.7, 6.7,                                                                  1749                                                             6.7Hz)       1685                                                             2.93(2H, ddd, J=6.7, 5.8,                                                                  1576                                                             1.0Hz)       1455                                                             3.67(1H, d, J=1.8Hz)                                                                       1382                                                             3.68(1H, d, J=1.8Hz)                                                                       1339                                                             5.17(1H, d, J=12.4Hz)                                                                      1268                                                             5.24(1H, d, J=12.4Hz)                                                                      1233                                                             7.40(5H, s)  1206                                                             8.42(1H, t, J=5.8Hz)                                                                       1164                                                                          988                                                                           893                                            6a      CH.sub.3 (CH.sub.2).sub.3                                                               0.87(3H, t, J=7.1Hz)                                                                       3287                                                                              (KBr)                                                        1.14˜1.49(4H, m)                                                                     1751                                                             3.09(2H, dt, J=5.6, 6.6Hz)                                                                 1657                                                             3.63(1H, d, J=1.8Hz)                                                                       1558                                                             3.68(1H, d, J=1.8Hz)                                                                       1347                                                             5.18(1H, d, J=12.8Hz)                                                                      1276                                                             5.24(1H, d, J=12.8Hz)                                                                      1256                                                             7.40(5H, s)  1230                                                             8.39(1H, t, J=5.6Hz)                                                                       1208                                                                          896                                            7a      (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                                     0.86(6H, d, J=6.6Hz)                                                                           (KBr)                                                        1.31(2H, dt, 6.8, 7.1Hz)                                                                   3276                                                             1.56(1H, tqq, J=6.8, 6.6,                                                                  1748                                                             6.6Hz)       1665                                                             3.11(2H, dt, J=5.3, 7.1Hz)                                                                 1575                                                             3.62(1H, d, J=1.9Hz)                                                                       1458                                                             3.67(1H, d, J=1.9Hz)                                                                       1385                                                             5.21(2H, s)  1347                                                             7.40(5H, s)  1278                                                             8.36(1H, t, J=5.3Hz)                                                                       1235                                                                          1203                                                                          895                                            8a      CH.sub.3 (CH.sub.2).sub.4                                                               0.86(3H, t, J=6.7Hz)                                                                       3317                                                                              (KBr)                                                        1.12˜1.52(6H, m)                                                                     2927                                                             3.01˜3.15(2H, m)                                                                     1749                                                             3.62(1H, d, J=1.8Hz)                                                                       1655                                                             3.68(1H, d, J=1.8Hz)                                                                       1573                                                             5.17(1H, d, J=12.7Hz)                                                                      1458                                                             5.24(1H, d, J=12.7Hz)                                                                      1375                                                             7.40(5H, s)  1342                                                             8.39(1H, t, J=5.6Hz)                                                                       1264                                                                          1231                                                                          1188                                                                          968                                                                           900                                            9a      CH.sub.3 (CH.sub.2).sub.5                                                               0.86(3H, t, J=6.5Hz)                                                                       3285                                                                              (KBr)                                                        1.14˜1.50(8H, m)                                                                     2926                                                             3.08(2H, dt, J=5.5, 6.5Hz)                                                                 1750                                                             3.62(1H, d, J=1.8Hz)                                                                       1737                                                             3.67(1H, d, J=1.8Hz)                                                                       1661                                                             5.20(2H, s)  1568                                                             7.39(5H, s)  1456                                                             8.39(1H, t, J=5.5Hz)                                                                       1379                                                                          1343                                                                          1293                                                                          1280                                                                          1198                                                                          1022                                                                          974                                                                           897                                            10a     CH.sub.3 (CH.sub.2).sub.6                                                               0.85(3H, t, J=6.5Hz)                                                                       3322                                                                              (KBr)                                                        1.10˜1.52(10H, m)                                                                    2925                                                             3.08(2H, dt, J=5.4, 6.5Hz)                                                                 1747                                                             3.62(1H, d, J=1.8Hz)                                                                       1651                                                             3.67(1H, d, J=1.8Hz)                                                                       1566                                                             5.20(2H, s)  1469                                                             7.39(5H, s)  1378                                                             8.38(1H, t, J=5.4Hz)                                                                       1343                                                                          1258                                                                          1231                                                                          1196                                                                          982                                                                           900                                            11a     PhCH.sub.2                                                                              3.71(1H, d, J=1.8Hz)                                                                       3288                                                                              (KBr)                                                        3.74(1H, d, J=1.8Hz)                                                                       1747                                                             4.31(2H, d, J=5.8Hz)                                                                       1656                                                             5.17(1H, d, J=12.4Hz)                                                                      1562                                                             5.24(1H, d, J=12.4Hz)                                                                      1456                                                             7.17˜7.50(10H, m)                                                                    1342                                                             8.93(1H, t, J=5.8Hz)                                                                       1264                                                                          1232                                                                          1191                                                                          902                                            12a     Ph        3.83(1H, d, J=1.8Hz)                                                                       3263                                                                              (KBr)                                                        3.87(1H, d, J=1.8Hz)                                                                       3066                                                             5.23(2H, s)  1750                                                             7.05˜7.16(1H, m)                                                                     1669                                                             7.27˜7.47(7H, m)                                                                     1547                                                             7.56˜7.67(2H, m)                                                                     1345                                                             10.48(1H, bs)                                                                              1234                                                                          1207                                                                          896                                            13a     C.sub.6 H.sub.11                                                                        1.05-1.80(10H, m)                                                                          3278                                                                              (KBr)                                                        3.45˜3.65(1H, m)                                                                     2928                                                             3.63(1H, d, J=1.8Hz)                                                                       1749                                                             3.67(1H, d, J=1.8Hz)                                                                       1659                                                             5.18(1H, d, J=12.3Hz)                                                                      1562                                                             5.24(1H, d, J=12.3Hz)                                                                      1345                                                             7.40(5H, s)  1227                                                             8.34(1H, d, J=7.9Hz)                                                                       1204                                                                          897                                            __________________________________________________________________________

Following the procedure and reaction conditions disclosed in Example 1busing Compounds 2a-13 a in Table 2, there were obtained thecorresponding compounds shown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________     ##STR6##                                                                     Compound No.                                                                          R.sup.1   NMR (DMSO-d.sub.6) δ(ppm)                                                            IR(cm.sup.-1)                                  __________________________________________________________________________    2b      CH.sub.3 CH.sub.2                                                                       1.03(3H, t, J=7.2Hz)                                                                       3320                                                                              (KBr)                                                        3.12(2H, dq, J=5.5, 7.2Hz)                                                                 2979                                                             3.47(1H, d, J=1.8Hz)                                                                       1769                                                             3.51(1H, d, J=1.8Hz)                                                                       1651                                                             8.35(1H, t, J=5.5Hz)                                                                       1579                                                             13.25˜13.70(1H, broad)                                                               1382                                                                          1362                                                                          894                                            3b      (CH.sub.3).sub.2 CH                                                                     1.07(6H, d, J=6.6Hz)                                                                       3333                                                                              (Neat)                                                       3.46(1H, d, J=1.8Hz)                                                                       2978                                                             3.50(1H, d, J=1.8Hz)                                                                       1742                                                             3.75˜3.98(1H, m)                                                                     1662                                                             8.27(1H, d, J=7.3Hz)                                                                       1556                                                             12.90˜13.90(1H, broad)                                                               1454                                                                          1235                                                                          897                                            4b      (CH.sub.3).sub.3 C                                                                      1.27(9H, s)  3347                                                                              (KBr)                                                        3.43(1H, d, J=1.8Hz)                                                                       2978                                                             3.54(1H, d, J=1.8Hz)                                                                       1737                                                             8.02(1H, bs) 1646                                                             13.05˜13.75(1H, broad)                                                               1563                                                                          1458                                                                          1395                                                                          1367                                                                          1328                                                                          1284                                                                          1216                                                                          894                                            5b      (CH.sub.3).sub.2 CHCH.sub.2                                                             0.84(6H, d, J=6.6Hz)                                                                       3310                                                                              (KBr)                                                        1.71(1H, tqq, J=6.4, 6.6,                                                                  1733                                                             6.6Hz)       1645                                                             2.93(2H, dd, J=5.5, 6.4Hz)                                                                 1563                                                             3.46(1H, d, J=1.9Hz)                                                                       1474                                                             3.57(1H, d, J=1.9Hz)                                                                       1326                                                             8.36(1H, t, J=5.5Hz)                                                                       1269                                                             13.20˜13.75(1H, broad)                                                               1230                                                                          993                                                                           892                                            6b      CH.sub.3 (CH.sub.2).sub.3                                                               0.87(3H, t, J=7.0Hz)                                                                       3335                                                                              (KBr)                                                        1.17˜1.50(4H, m)                                                                     3277                                                             3.09(2H, dt, J=5.5, 6.4Hz)                                                                 2962                                                             3.46(1H, d, J=1.9Hz)                                                                       1742                                                             3.53(1H, d, J=1.9Hz)                                                                       1662                                                             8.33(1H, t, J=5.5Hz)                                                                       1574                                                             13.46(1H, bs)                                                                              1454                                                                          1385                                                                          1313                                                                          1242                                                                          892                                            7b      (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                                     0.87(6H, d, J=6.6Hz)                                                                       3335                                                                              (KBr)                                                        1.31(2H, dt, J=6.8, 7.5Hz)                                                                 3273                                                             1.57(1H, tqq, J=6.8, 6.6,                                                                  2960                                                             6.6Hz)       1742                                                             3.11(2H, dt, J=5.5, 7.5Hz)                                                                 1661                                                             3.45(1H, d, J=1.9Hz)                                                                       1576                                                             3.52(1H, d, J=1.9Hz)                                                                       1454                                                             8.31(1H, t, J=5.5Hz)                                                                       1386                                                             13.20˜13.75(1H, broad)                                                               1311                                                                          1242                                                                          892                                            8b      CH.sub.3 (CH.sub.2).sub.4                                                               0.86(3H, t, J=6.7Hz)                                                                       3339                                                                              (KBr)                                                        1.12˜1.55(6H, m)                                                                     3267                                                             3.08(2H, dt, J=5.5, 6.7Hz)                                                                 2952                                                             3.46(1H, d, J=1.8Hz)                                                                       2863                                                             3.53(1H, d, J=1.8Hz)                                                                       1742                                                             8.34(1H, t, J=5.5Hz)                                                                       1719                                                             13.25˜13.65(1H, broad)                                                               1661                                                                          1627                                                                          1577                                                                          1456                                                                          1397                                                                          1281                                                                          1242                                                                          1193                                                                          895                                            9b      CH.sub.3 (CH.sub.2).sub.5                                                               0.86(3H, t, J=6.5Hz)                                                                       3337                                                                              (KBr)                                                        1.13˜1.50(8H, m)                                                                     3264                                                             3.08(2H, dt, J=5.5, 6.5Hz)                                                                 2957                                                             3.45(1H, d, J=1.8Hz)                                                                       2930                                                             3.52(1H, d, J=1.8Hz)                                                                       1742                                                             8.33(1H, t, J=5.5Hz)                                                                       1724                                                             13.25˜13.60(1H, broad)                                                               1661                                                                          1631                                                                          1579                                                                          1455                                                                          1397                                                                          1242                                                                          1191                                                                          894                                            10b     CH.sub.3 (CH.sub.2).sub.6                                                               0.86(3H, t, J=6.5Hz)                                                                       3259                                                                              (KBr)                                                        1.12˜1.55(10H, m)                                                                    2921                                                             3.08(2H, dt, J=5.5, 6.5Hz)                                                                 1734                                                             3.45(1H, d, J=1.9Hz)                                                                       1693                                                             3.52(1H, d, J=1.9Hz)                                                                       1662                                                             8.32(1H, t, J=5.5Hz)                                                                       1576                                                             13.30˜13.60(1H, broad)                                                               1465                                                                          1392                                                                          1262                                                                          1225                                                                          888                                            11b     PhCH.sub.2                                                                              3.52(1H, d, J=1.8Hz)                                                                       3294                                                                              (KBr)                                                        3.61(1H, d, J=1.8Hz)                                                                       1745                                                             4.32(2H, d, J=5.9Hz)                                                                       1665                                                             7.19˜7.39(5H, m)                                                                     1568                                                             8.89(1H, t, J=5.9Hz)                                                                       1455                                                             13.10˜13.80(1H, broad)                                                               1388                                                                          1263                                                                          1239                                                                          891                                            12b     Ph        3.62(1H, d, J=1.8Hz)                                                                       3353                                                                              (KBr)                                                        3.78(1H, d, J=1.8Hz)                                                                       3270                                                             7.02˜7.19(1H, m)                                                                     1752                                                             7.25˜7.43(2H, m)                                                                     1731                                                             7.55˜7.68(2H, m)                                                                     1675                                                             10.42(1H, bs)                                                                              1605                                                             13.00˜14.00(1H, broad)                                                               1551                                                                          1446                                                                          1216                                                                          903                                            13b     C.sub.6 H.sub.11                                                                        1.00˜1.90(10H, m)                                                                    3305                                                                              (KBr)                                                        3.41˜3.68(1H, m)                                                                     2937                                                             3.45(1H, d, J=1.9Hz)                                                                       1728                                                             3.53(1H, d, J=1.9Hz)                                                                       1636                                                             8.29(1H, d, J=7.9Hz)                                                                       1576                                                             13.15˜13.75(1H, broad)                                                               1452                                                                          1332                                                                          1266                                                                          1220                                                                          1153                                                                          993                                                                           895                                            __________________________________________________________________________

Following the procedure and reaction conditions disclosed in Example 1cusing Compounds 1b-13b in Table 3, there were obtained the correspondingcompounds shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________     ##STR7##                                                                     Compound No.                                                                          R.sup.1   NMR (DMSO-d.sub.6) δ(ppm)                                                            IR(cm.sup.-1)                                                                       MS(FAB) (M/Z)                            __________________________________________________________________________    2c      CH.sub.3 CH.sub.2                                                                       0.79(3H, t, J=7.3Hz)                                                                       (KBr) 460(MH.sup.+)                                              0.86(3H, d, J=6.9Hz)                                                                       3292                                                             0.96˜1.22(1H, m)                                                                     2970                                                             1.02(3H, t, J=7.2Hz)                                                                       1746                                                             1.36˜1.60(1H, m)                                                                     1630                                                             1.68˜2.32(5H, m)                                                                     1546                                                             3.11(2H, dq, J=5.7,                                                                        1453                                                             7.2Hz)       1273                                                             3.45(1H, d, J=1.8Hz)                                                                       1171                                                             3.53˜3.85(2H, m)                                                                      894                                                             3.65(1H, d, J=1.8Hz)                                                          4.35˜4.48(2H, m)                                                        5.12(2H, s)                                                                   7.36(5H, s)                                                                   8.35(1H, t, J=5.7Hz)                                                          8.77(1H, d, J=8.6Hz)                                        3c      (CH.sub.3).sub.2 CH                                                                     0.79(3H, t, J=7.4Hz)                                                                       (KBr) 474(MH.sup.+)                                              0.89(3H, d, J=6.8Hz)                                                                       3282                                                             0.95˜1.25(1H, m)                                                                     2971                                                             1.07(6H, d, J=6.6Hz)                                                                       1747                                                             1.33-1.63(1H, m)                                                                           1630                                                             1.65˜2.28(5H, m)                                                                     1541                                                             3.45(1H, d, J=1.8Hz)                                                                       1456                                                             3.52˜3.98(3H, m)                                                                     1277                                                             3.65(1H, d, J=1.8Hz)                                                                       1172                                                             4.33˜4.48(2H, m)                                                                      896                                                             5.12(2H, s)                                                                   7.36(5H, s)                                                                   8.26(1H, d, J=7.7Hz)                                                          8.73(1H, d, J=8.4Hz)                                        4c      (CH.sub.3).sub.3 C                                                                      0.79(3H, t, J=7.4Hz)                                                                       (KBr) 488(MH.sup.+)                                              0.86(3H, d, J=6.7Hz)                                                                       3282                                                             0.96˜1.20(1H, m)                                                                     2969                                                             1.26(9H, s)  1747                                                             1.36˜1.60(1H, m)                                                                     1687                                                             1.65˜2.00(4H, m)                                                                     1630                                                             2.10˜2.28(1H, m)                                                                     1535                                                             3.49(1H, d, J=1.8Hz)                                                                       1455                                                             3.53˜3.68(1H, m)                                                                     1365                                                             3.63(1H, d, J=1.8Hz)                                                                       1278                                                             3.71˜3.85(1H, m)                                                                     1216                                                             4.35˜4.47(1H, m)                                                                     1170                                                             5.11(2H, s)   894                                                             7.36(5H, s)                                                                   8.03(1H, bs)                                                                  8.72(1H, d, J=8.4Hz)                                        5c      (CH.sub.3).sub.2 CHCH.sub.2                                                             0.74˜0.96(12H, m)                                                                    (KBr) 488(MH.sup.+)                                              0.97˜1.20(1H, m)                                                                     3289                                                             1.37˜1.57(1H, m)                                                                     2963                                                             1.59˜2.00(5H, m)                                                                     1747                                                             2.09˜2.30(1H, m)                                                                     1631                                                             2.77˜3.06(2H, m)                                                                     1541                                                             3.51(1H, d, J=1.8Hz)                                                                       1455                                                             3.54˜3.69(1H, m)                                                                     1386                                                             3.66(1H, d, J=1.8Hz)                                                                       1352                                                             3.71˜3.85(1H, m)                                                                     1276                                                             4.34˜5.00(2H, m)                                                                     1171                                                             5.12(2H, s)   900                                                             7.36(5H, s)                                                                   8.32(1H, t, J=6.0Hz)                                                          8.78(1H, d, J=8.4Hz)                                        6c      CH.sub.3 (CH.sub.2).sub.3                                                               0.79(3H, t, J=7.3Hz)                                                                       (CHCl.sub.3)                                                                        488(MH.sup.+)                                              0.85(3H, d, J=6.8Hz)                                                                       3416                                                             0.86(3H, t, J=6.8Hz)                                                                       3013                                                             0.95˜1.60(6H, m)                                                                     2966                                                             1.66˜2.02(4H, m)                                                                     1742                                                             2.10˜2.30(1H, m)                                                                     1684                                                             2.98˜3.18(2H, m)                                                                     1642                                                             3.47(1H, d, J=1.8Hz)                                                                       1520                                                             3.53˜3.69(1H, m)                                                                     1448                                                             3.65(1H, d, J=1.8Hz)                                                                       1384                                                             3.70˜3.85(1H, m)                                                                     1353                                                             4.30˜4.50(2H, m)                                                                     1276                                                             5.12(2H, s)  1237                                                             7.36(5H, s)  1174                                                             8.31(1H, t, J=5.6Hz)                                                                       1107                                                             8.76(1H, d, J=8.5Hz)                                                                        897                                           7c      (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                                     0.72˜0.93(12H, m)                                                                    (CHCl.sub.3)                                                                        502(MH.sup.+)                                              0.94˜1.20(1H, m)                                                                     3415                                                             1.23˜1.37(2H, m)                                                                     3013                                                             1.38˜1.66(2H, m)                                                                     2964                                                             1.68˜2.02(4H, m)                                                                     1742                                                             2.10˜2.30(1H, m)                                                                     1684                                                             3.00˜3.20(2H, m)                                                                     1645                                                             3.46(1H, d, J=1.8Hz)                                                                       1520                                                             3.50˜3.69(1H, m)                                                                     1447                                                             3.64(1H, d, J=1.8Hz)                                                                       1237                                                             3.70˜3.86(1H, m)                                                                     1173                                                             4.35˜4.48(2H, m)                                                                     1107                                                             5.12(2H, s)   896                                                             7.36(5H, s)                                                                   8.29(1H, t, J=5.7Hz)                                                          8.76(1H, d, J=8.4Hz)                                        8c      CH.sub.3 (CH.sub.2).sub.4                                                               0.80(3H, t, J=7.3Hz)                                                                       (CHCl.sub.3)                                                                        502(MH.sup.+)                                              0.85(3H, d, J=6.8Hz)                                                                       3416                                                             0.86(3H, t, J=6.4Hz)                                                                       3012                                                             0.98˜1.59(8H, m)                                                                     2965                                                             1.67˜2.02(4H, m)                                                                     1743                                                             2.10˜2.28(1H, m)                                                                     1685                                                             2.97˜3.17(2H, m)                                                                     1645                                                             3.47(1H, d, J=1.8Hz)                                                                       1520                                                             3.54˜3.69(1H, m)                                                                     1446                                                             3.65(1H, d, J=1.8Hz)                                                                       1384                                                             3.70˜ 3.86(1H, m)                                                                    1353                                                             4.34˜4.50(2H, m)                                                                     1237                                                             5.12(2H, s)  1174                                                             7.36(5H, s)  1107                                                             8.32(1H, t, J=5.7Hz)                                                                        898                                                             8.76(1H, d, J=8.5Hz)                                        9c      CH.sub.3 (CH.sub.2).sub.5                                                               0.80(3H, t, J=7.2Hz)                                                                       (CHCl.sub.3)                                                                        516(MH.sup.+)                                              0.85(3H, d, J=6.9Hz)                                                                       3416                                                             0.86(3H, t, J=6.0Hz)                                                                       2965                                                             0.95˜1.60(10H, m)                                                                    2933                                                             1.65˜2.02(4H, m)                                                                     1742                                                             2.10˜2.30(1H, m)                                                                     1685                                                             3.00˜3.15(2H, m)                                                                     1645                                                             3.47(1H, d, J=1.8Hz)                                                                       1520                                                             3.52˜3.69(1H, m)                                                                     1446                                                             3.64(1H, d, J=1.8Hz)                                                                       1238                                                             3.70˜3.85(1H, m)                                                                     1173                                                             4.34˜4.50(2H, m)                                                                     1107                                                             5.12(2H, s)   898                                                             7.36(5H, s)                                                                   8.32(1H, t, J=5.9Hz)                                                          8.75(1H, d, J=8.2Hz)                                        10c     CH.sub.3 (CH.sub.2).sub.6                                                               0.80(3H, t, J=7.3Hz)                                                                       (CHCl.sub.3)                                                                        530(MH.sup.+)                                              0.86(3H, d, J=6.8Hz)                                                                       3417                                                             0.86(3H, t, J=5.6Hz)                                                                       3013                                                             0.95˜1.60(12H, m)                                                                    2964                                                             1.65˜2.02(4H, m)                                                                     2932                                                             2.10˜2.28(1H, m)                                                                     1742                                                             2.98˜3.16(2H, m)                                                                     1685                                                             3.47(1H, d, J=1.8Hz)                                                                       1645                                                             3.52˜3.69(1H, m)                                                                     1520                                                             3.64(1H, d, J=1.8Hz)                                                                       1446                                                             3.70˜3.85(1H, m)                                                                     1237                                                             4.34˜4.51(2H, m)                                                                     1107                                                             5.12(2H, s)   897                                                             7.36(5H, s)                                                                   8.32(1H, t, J=5.6Hz)                                                          8.75(1H, d, J=8.4Hz)                                        11c     PhCH.sub.2                                                                              0.80(3H, t, J=7.4Hz)                                                                       (KBr) 522(MH.sup.+)                                              0.86(3H, d, J=6.8Hz)                                                                       3286                                                             0.95˜1.25(1H, m)                                                                     2966                                                             1.36˜1.60(1H, m)                                                                     1746                                                             1.65˜2.03(4H, m)                                                                     1679                                                             2.10˜2.30(1H, m)                                                                     1628                                                             3.55(1H, d, J=1.8Hz)                                                                       1536                                                             3.56˜3.69(1H, m)                                                                     1455                                                             3.71(1H, d, J=1.8Hz)                                                                       1384                                                             3.72˜3.86(1H, m)                                                                     1352                                                             4.20˜4.50(4H, m)                                                                     1276                                                             5.13(2H, s)  1170                                                             7.20˜7.50(10H, m)                                                                    1096                                                             8.80(1H, t, J=8.4Hz)                                                                       1029                                                             8.88(1H, t, J=5.9Hz)                                                                        899                                           12c     Ph        0.81(3H, t, J=7.5Hz)                                                                       (KBr) 508(MH.sup.+)                                              0.87(3H, d, J=6.8Hz)                                                                       3279                                                             0.97˜1.25(1H, m)                                                                     2965                                                             1.38˜1.63(1H, m)                                                                     1746                                                             1.67˜1.98(4H, m)                                                                     1693                                                             2.09˜2.30(1H, m)                                                                     1626                                                             3.54˜3.88(2H, m)                                                                     1537                                                             3.72(1H, d, J=1.7Hz)                                                                       1446                                                             3.79(1H, d, J=1.7Hz)                                                                       1168                                                             4.33˜4.55(2H, m)                                                                      895                                                             5.12(2H, s)                                                                   7.02˜7.16(1H, m)                                                        7.20˜7.50(7H, m)                                                        7.55˜7.70(2H, m)                                                        8.82(1H, d, J=8.5Hz)                                                          10.45(1H, s)                                                13c     C.sub.6 H.sub.11                                                                        0.80(3H, t, J=7.3Hz)                                                                       (KBr) 514(MH.sup.+)                                              0.87(3H, d, J=6.8Hz)                                                                       3283                                                             0.96˜1.97(16H, m)                                                                    2933                                                             2.09˜2.30(1H, m)                                                                     2856                                                             3.48(1H, d, J=1.7Hz)                                                                       1747                                                             3.51˜3.64(2H, m)                                                                     1631                                                             3.65(1H, d, J=1.7Hz)                                                                       1536                                                             3.70˜3.86(1H, m)                                                                     1452                                                             4.35˜4.49(2H, m)                                                                      898                                                             5.12(2H, s)                                                                   7.36(5H, s)                                                                   8.30(1H, d, J=7.9Hz)                                                          8.76(1H, d, J=8.6Hz)                                        __________________________________________________________________________

Following the procedure and reaction conditions disclosed in Example 1dusing Compounds 2c-13c in Table 3, there were obtained the correspondingcompounds shown in Table 5.

                                      TABLE 5                                     __________________________________________________________________________     ##STR8##                                                                     Compound No.                                                                          R.sup.1   NMR (DMSO-d.sub.6) δ(ppm)                                                           IR(cm.sup.-1)                                                                       MS(FAB) (M/Z)                             __________________________________________________________________________    2d      CH.sub.3 CH.sub.2                                                                       0.83(3H, t, J=7.2Hz)                                                                      (KBr) 370(MH.sup.+)                                               0.92(3H, d, J=6.8Hz)                                                                      3286                                                              0.95˜1.25(1H, m)                                                                    2971                                                              1.02(3H, t, J=7.1Hz)                                                                      1739                                                              1.38˜1.62(1H, m)                                                                    1631                                                              1.65˜2.30(5H, m)                                                                    1541                                                              3.14(2H, dq, J=5.6,                                                                       1451                                                              7.1Hz)      1190                                                              3.45(1H, d, J=1.8Hz)                                                                       894                                                              3.50˜3.85(2H, m)                                                        3.65(1H, d, J=1.8Hz)                                                          4.20˜4.31(1H, m)                                                        4.42(1H, dd, J=8.5,                                                           8.5Hz)                                                                        8.35(1H, t, J=5.6Hz)                                                          8.72(1H, d, J=8.5Hz)                                                          12.20˜12.80(1H, broad)                                3d      (CH.sub.3).sub.2 CH                                                                     0.83(3H, t, J=7.3Hz)                                                                      (KBr) 384(MH.sup.+ )                                              0.92(3H, d, J=6.8Hz)                                                                      3283                                                              1.00˜1.30(1H, m)                                                                    2973                                                              1.07(6H, d, J=6.6Hz)                                                                      1738                                                              1.35˜1.63(1H, m)                                                                    1630                                                              1.65˜2.25(5H, m)                                                                    1545                                                              3.45(1H, d, J=1.8Hz)                                                                      1453                                                              3.50˜3.96(3H, m)                                                                    1370                                                              3.65(1H, d, J=1.8Hz)                                                                      1242                                                              4.20˜4.30(1H, m)                                                                    1191                                                              4.41(1H, dd, J=8.5,                                                                        897                                                              8.5Hz)                                                                        8.27(1H, d, J=7.6Hz)                                                          8.71(1H, d, J=8.5Hz)                                                          12.30˜12.75(1H, broad)                                4d      (CH.sub.3).sub.3 C                                                                      0.83(3H, t, J=7.3Hz)                                                                      (KBr) 398(MH.sup.+)                                               0.92(3H, d, J=6.7Hz)                                                                      3304                                                              0.95˜1.25(1H, m)                                                                    2970                                                              1.27(9H, s) 1739                                                              1.40˜1.62(1H, m)                                                                    1631                                                              1.68˜2.03(4H, m)                                                                    1536                                                              2.05˜2.22(1H, m)                                                                    1455                                                              3.49(1H, d, J=1.8Hz)                                                                      1395                                                              3.52˜3.68(1H, m)                                                                    1367                                                              3.63(1H, d, J=1.8Hz)                                                                      1323                                                              3.69˜3.83(1H, m)                                                                    1222                                                              4.18˜4.29(1H, m)                                                                    1190                                                              4.41(1H, dd, J=8.4,                                                                        895                                                              8.4Hz)                                                                        8.03(1H, s)                                                                   8.69(1H, d, J=8.4Hz)                                                          12.35˜12.65(1H, broad)                                5d      (CH.sub. 3).sub.2 CHCH.sub.2                                                            0.83(3H, t, J=6.9Hz)                                                                      (KBr) 398(MH.sup.+)                                               0.84(6H, d, J=6.8Hz)                                                                      3286                                                              0.92(3H, d, J=6.6Hz)                                                                      2965                                                              0.98˜1.24(1H, m)                                                                    1738                                                              1.38˜1.60(1H, m)                                                                    1630                                                              1.60˜2.02(5H, m)                                                                    1543                                                              2.03˜2.25(1H, m)                                                                    1452                                                              2.79˜3.05(2H, m)                                                                    1190                                                              3.51(1H, d, J=1.8Hz)                                                                       900                                                              3.52˜3.68(1H, m)                                                        3.66(1H, d, J=1.8Hz)                                                          3.68˜3.83(1H, m)                                                        4.20˜4.30(1H, m)                                                        4.43(1H, dd, J=8.5,                                                           8.5Hz)                                                                        8.33(1H, t, J=6.0Hz)                                                          8.76(1H, d, J=8.5Hz)                                                          12.25˜12.75(1H, broad)                                6d      CH.sub.3 (CH.sub.2).sub.3                                                               0.80˜1.02(9H, m)                                                                    (KBr) 398(MH.sup.+)                                               1.03˜1.66(6H, m)                                                                    3284                                                              1.70˜2.07(4H, m)                                                                    2964                                                              2.08˜2.32(1H, m)                                                                    1739                                                              3.00˜3.23(2H, m)                                                                    1628                                                              3.52(1H, d, J=1.8Hz)                                                                      1542                                                              3.56˜3.88(2H, m)                                                                    1452                                                              3.70(1H, d, J=1.8Hz)                                                                      1321                                                              4.24˜4.35(1H, m)                                                                    1226                                                              4.47(1H, dd, J=8.5,                                                                       1190                                                              8.5Hz)       895                                                              8.36(1H, t, J=5.7Hz)                                                          8.79(1H, d, J=8.5Hz)                                                          12.35˜12.80(1H, broad)                                7d      (CH.sub.3).sub.2 CH(CH.sub.2).sub.2                                                     0.83(3H, t, J=7.4Hz)                                                                      (KBr) 412(MH.sup.+)                                               0.86(6H, d, J=6.6Hz)                                                                      3287                                                              0.92(3H, d, J=6.8Hz)                                                                      2962                                                              0.98˜1.20(1H, m)                                                                    1739                                                              1.23˜1.38(2H, m)                                                                    1631                                                              1.40˜1.67(2H, m)                                                                    1541                                                              1.68˜2.02(4H, m)                                                                    1453                                                              2.05˜2.24(1H, m)                                                                    1386                                                              3.00˜3.21(2H, m)                                                                    1227                                                              3.46(1H, d, J=1.8Hz)                                                                      1189                                                              3.52˜3.68(1H, m)                                                                     895                                                              3.64(1H, d, J=1.8Hz)                                                          3.68˜3.83(1H, m)                                                        4.20˜4.30(1H, m)                                                        4.42(1H, dd, J=8.4,                                                           8.6Hz)                                                                        8.30(1H, t, J=5.8Hz)                                                          8.74(1H, d, J=8.4Hz)                                                          12.35˜12.65(1H, broad)                                8d      CH.sub.3 (CH.sub.2).sub.4                                                               0.83(3H, t, J=6.9Hz)                                                                      (KBr) 412(MH.sup.+)                                               0.86(3H, t, J=6.7Hz)                                                                      3286                                                              0.92(3H, d, J=6.8Hz)                                                                      2963                                                              0.98˜1.63(8H, m)                                                                    2934                                                              1.65˜2.03(4H, m)                                                                    1740                                                              2.05˜2.25(1H, m)                                                                    1628                                                              2.93˜3.15(2H, m)                                                                    1541                                                              3.47(1H, d, J=1.8Hz)                                                                      1454                                                              3.55˜3.84(2H, m)                                                                    1322                                                              3.65(1H, d, J=1.8Hz)                                                                      1190                                                              4.20˜4.25(1H, m)                                                                     897                                                              4.42(1H, dd, J=8.6,                                                           8.6Hz)                                                                        8.32(1H, t, J=5.6Hz)                                                          8.72(1H, d, J=8.6Hz)                                                          12.30˜12.80(1H, broad)                                9d      CH.sub.3 (CH.sub.2).sub.5                                                               0.83(3H, t, J=6.8Hz)                                                                      (KBr) 426(MH.sup.+)                                               0.86(3H, t, J=6.5Hz)                                                                      3284                                                              0.92(3H, d, J=6.8Hz)                                                                      2962                                                              0.98˜1.62(10H, m)                                                                   2933                                                              1.67˜2.02(4H, m)                                                                    1739                                                              2.06˜2.25(1H, m)                                                                    1629                                                              3.00˜3.14(2H, m)                                                                    1542                                                              3.47(1H, d, J=1.8Hz)                                                                      1454                                                              3.52˜3.68(1H, m)                                                                    1322                                                              3.64(1H, d, J=1.8Hz)                                                                      1191                                                              3.69˜3.84(1H, m)                                                                     898                                                              4.19˜4.30(1H, m)                                                        4.42(1H, dd, J=8.4,                                                           8.6Hz)                                                                        8.33(1H, t, J=5.6Hz)                                                          8.73(1H, d, J=8.4Hz)                                                          12.30˜12.75(1H, broad)                                10d     CH.sub.3 (CH.sub.2).sub.6                                                               0.83(3H, t, J=6.7Hz)                                                                      (KBr) 440(MH.sup.+)                                               0.86(3H, t, J=6.5Hz)                                                                      3285                                                              0.92(3H, d, J=6.8Hz)                                                                      2962                                                              0.97˜1.62(12H, m)                                                                   2931                                                              1.67˜2.00(4H, m)                                                                    1743                                                              2.06˜2.26(1H, m)                                                                    1628                                                              2.97˜3.15(2H, m)                                                                    1542                                                              3.47(1H, d, J=1.8Hz)                                                                      1455                                                              3.52˜3.68(1H, m)                                                                    1322                                                              3.64(1H, d, J=1.8Hz)                                                                      1189                                                              3.68˜3.83(1H, m)                                                                     896                                                              4.20˜4.31(1H, m)                                                        4.42(1H, dd, J=8.6,                                                           8.6Hz)                                                                        8.32(1H, t, J=5.6Hz)                                                          8.73(1H, d, J=8.6Hz)                                                          12.35˜12.70(1H, broad)                                11d     PhCH.sub.2                                                                              0.83(3H, t, J=7.3Hz)                                                                      (KBr) 432(MH.sup.+)                                               0.92(3H, d, J=6.6Hz)                                                                      3286                                                              0.95˜1.28(1H, m)                                                                    2968                                                              1.38˜1.63(1H, m)                                                                    1739                                                              1.65˜2.03(4H, m)                                                                    1627                                                              2.07˜2.24(1H, m)                                                                    1537                                                              3.50˜3.66(1H, m)                                                                    1455                                                              3.55(1H, d, J=1.9Hz)                                                                      1323                                                              3.68˜3.85(1H, m)                                                                    1227                                                              3.71(1H, d, J=1.9Hz)                                                                      1189                                                              4.15˜4.50(4H, m)                                                                     898                                                              7.20˜7.40(5H, m)                                                        8.75(1H, d, J=8.4Hz)                                                          8.87(1H, t, J=5.9Hz)                                                          12.30˜12.80(1H, broad)                                12d     Ph        0.85(3H, t, J=7.3Hz)                                                                      (KBr) 418(MH.sup.+)                                               0.94(3H, d, J=6.6Hz)                                                                      3338                                                              0.97˜1.30(1H, m)                                                                    3274                                                              1.41˜1.64(1H, m)                                                                    2969                                                              1.64˜2.02(4H, m)                                                                    1697                                                              2.04˜2.24(1H, m)                                                                    1674                                                              3.50˜3.90(2H, m)                                                                    1619                                                              3.73(1H, d, J=1.7Hz)                                                                      1548                                                              3.79(1H, d, J=1.7Hz)                                                                      1447                                                              4.17˜4.32(1H, m)                                                                    1190                                                              4.35˜4.54(1H, m)                                                                     897                                                              7.02˜7.16(1H, m)                                                        7.24˜7.40(2H, m)                                                        7.54˜7.70(2H, m)                                                        8.82(1H, d, J=8.4Hz)                                                          10.42(1H, s)                                                                  12.25˜12.75(1H, broad)                                13d     C.sub.6 H.sub.11                                                                        0.82(3H, t, J=7.2Hz)                                                                      (KBr) 424(MH.sup.+)                                               0.94(3H, d, J=6.6Hz)                                                                      3291                                                              1.06˜2.02(16H, m)                                                                   2934                                                              2.05˜2.24(1H, m)                                                                    2857                                                              3.48(1H, d, J=1.7Hz)                                                                      1743                                                              3.50˜3.63(2H, m)                                                                    1631                                                              3.65(1H, d, J=1.7Hz)                                                                      1537                                                              3.67˜3.86(1H, m)                                                                    1451                                                              4.20˜4.30(1H, m)                                                                     894                                                              4.30˜4.49(1H, m)                                                        8.31(1H, d, J=7.9Hz)                                                          8.75(1H, d, J=8.4Hz)                                                          12.30˜12.75(1H, broad)                                __________________________________________________________________________

INDUSTRIAL UTILIZATION

For use of the compounds of Formula I for the treatment of muscularatrophy diseases, the compounds of the present invention areadministered orally or parenterally in the dosage form of tablets,pills, capsules, granules and injectional solutions. These preparationscan be prepared according to the conventional practices using ordinaryadditives such as fillers, binders, disintegrators, pH adjusting agentsand solubilizers.

The dosage of the compound of Formula I for therapy to a patient dependson the age of the patient and kind and conditions of the diseases, butusually it is in the range from 10 to 2000 mg in single or severaldivided doses per day.

We claim:
 1. An epoxysuccinamic acid derivative represented by theformula: ##STR9## wherein R¹ is an alkyl group having 1 to 10 carbonatoms, a phenyl group or a benzyl group or a pharmaceutically acceptablesalt thereof.
 2. An epoxysuccinamic acid derivative according to claim 1wherein the compound of Formula I isN-(L-3-trans-n-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline.3. An epoxysuccinamic acid derivative according to claim 1 wherein thecompound of Formula I isN-(L-3-trans-n-pentylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline.4. An epoxysuccinamic acid derivative represented by the formula:##STR10## wherein R¹ is an alkyl group having 1 to 10 carbon atoms, aphenyl group or a benzyl group, and R² is a protecting group of thecarboxyl group.